Translational Therapeutics

Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1

Abstract

Background

Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years.

Methods

Using multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry.

Results

Chemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells.

Conclusions

Targeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

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Fig. 1: Chemotherapy exacerbated the migration of ovarian cancer cell lines.
Fig. 2: Chemotherapy induced the cancer stem cell (CSC)-like characteristics of ovarian cancer cell lines.
Fig. 3: Expression of the pluripotency-associated genes, OCSC markers and EMT markers after the chemotherapy treatments.
Fig. 4: The chemotherapy-exacerbated cancer stem cell-like property increase is associated with the expression of GLI1.
Fig. 5: Downregulating GLI1 inhibited the chemotherapy-exacerbated CSC-like property increase and migration in ovarian cancer cells.
Fig. 6: Chemotherapy induced the CSC-like properties of ovarian cancer cell lines through GLI1–BMI1 signalling pathway.

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Acknowledgements

We thank professor Ming Zhang and professor Weiyang Zhang for the advice and the technical assistance.

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Affiliations

Authors

Contributions

Y.Z., professor L.C., professor K.H. and professor J.L. designed the study. Y.Z., T.S., M.G., M.Z., F.Y., X.Z. and X.Y. carried out the experiments. Y.Z. and M.H. wrote the paper. Professor K.H., Dr D.S. and Dr Y.P. revised the paper. Dr L.C. gave assistance to the tissue sample collection. Y.Z., M.H. and Y.J. analysed data. All authors read and approved the final version of the paper.

Corresponding authors

Correspondence to Kan He or Li Chen.

Ethics declarations

Ethics approval and consent to participate

The collection of ovarian cancer tissue was approved by the Ethics Committee of Jilin Cancer Hospital and performed in accordance with the Declaration of Helsinki. All patients signed written informed consent before participating in this study. The SKOV-3 and A2780 cell lines were purchased from The Cell Bank of Chinese Academy of Sciences (Shanghai, China). The KURAMOCHI cell line was purchased from Japanese Collection of Research Bioresources (JCRB) Cell Bank.

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Not applicable.

Data availability

The datasets used and/or analysed during this study are available from the corresponding author on reasonable request. The RNA-seq dataset GSE109934 is available in the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/).27 The survival analysis was performed using the PROGgeneV2 website tool (http://watson.compbio.iupui.edu/chirayu/proggene/database/?url=proggene).28

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The authors declare no competing interests.

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Zhao, Y., He, M., Cui, L. et al. Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1. Br J Cancer 122, 1638–1648 (2020). https://doi.org/10.1038/s41416-020-0825-7

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